Key result
Biglycan deficiency causes spontaneous aortic dissection and rupture, driving ~50% sudden death in male mice.
Why the study?
The cause of most spontaneous aortic dissections and ruptures is unknown, though pedigree analyses suggest possible X-linked inheritance. A vascular phenotype had never been described in mice deficient in the X-linked biglycan gene, which encodes a small leucine-rich proteoglycan involved in extracellular matrix integrity.
Hypothesis-generating for biglycan in aortic integrity; clinical relevance in humans remains undetermined.
BACKGROUND: For the majority of cases, the cause of spontaneous aortic dissection and rupture is unknown. An inherited risk is associated with Marfan syndrome, Ehlers-Danlos syndrome type IV, and loci mapped to diverse autosomal chromosomes. Analysis of pedigrees however has indicated that it may be also inherited as an X-linked trait. The biglycan gene, found on chromosome X in humans and mice, encodes a small leucine-rich proteoglycan involved in the integrity of the extracellular matrix. A vascular phenotype has never been described in mice deficient in the gene for small leucine-rich proteoglycans. In the breeding of BALB/cA mice homozygous for a null mutation of the biglycan gene, we observed that 50% of biglycan-deficient male mice died suddenly within the first 3 months of life. METHODS AND RESULTS: Necropsies revealed a major hemorrhage in the thoracic or abdominal cavity, and histology showed aortic rupture that involved an intimal and medial tear as well as dissection between the media and adventitia. By transmission electron microscopy and biomechanical testing, the aortas of biglycan-deficient mice showed structural abnormalities of collagen fibrils and reduced tensile strength. Similar collagen fibril changes were observed in male as well as in female biglycan-deficient mice, which implies a role of additional determinants such as gender-related response to stress in the development of this vascular catastrophe only in male mice. CONCLUSIONS: The spontaneous death of biglycan-deficient male mice from aortic rupture implicates biglycan as essential for the structural and functional integrity of the aortic wall and suggests a potential role of biglycan gene defects in the pathogenesis of aortic dissection and rupture in humans.
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Heegaard et al. (2007) studied Spontaneous aortic dissection and rupture. Biglycan gene null mutation (biglycan deficiency) vs. Female biglycan-deficient mice was evaluated on Sudden death from spontaneous aortic dissection and rupture within the first 3 months of life. Biglycan deficiency in male BALB/cA mice caused spontaneous aortic dissection and rupture leading to sudden death in 50% of animals within the first 3 months of life.
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